Modified Vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that cannot replicate in human cells. It is expected to have a better safety profile than the traditional smallpox vaccines. The IND for this study agent was submitted to the FDA in FY 02 and the first clinical study was initiated on 12/19/02. There are two clinical trials. They are phase I/II, randomized, placebo-controlled, double-blinded, schedule-finding studies of MVA. VRC 201 is being done with healthy young adults who are vaccinia-naive, and VRC 203 with healthy adults who were vaccinated against smallpox more than 10 years ago. The hypothesis is that MVA will be safe in humans when administered by intramuscular injection and will result in an immune response comparable to that observed after Dryvax primary vaccination. Subjects were randomized to different primary immunization schedules either with Dryvax or with MVA or placebo. Each schedule included a Dryvax challenge 12 weeks after completion of the primary vaccination schedule. Safety evaluations were performed on an ongoing basis throughout the studies and immunogenicity samples were collected and frozen for batch testing by research laboratories. VRC 201 was closed to accrual in June 2004 with 77 of the target 105 subjects enrolled. The Intramural Data and Safety Monitoring Board completed its final review of interim safety data in December 2004 and the study was completed in January 2005. VRC 203 was closed to accrual in June 2004 with 75 of the target 80 subjects enrolled. The Intramural Data and Safety Monitoring Board completed its final review of interim safety data in December 2004 and the study was completed in February 2005.